3Beta-hydroxy-6-aza-cholestane and related analogues as phosphatidylinositol specific phospholipase C (PI-PLC) inhibitors with antitumor activity

Bioorg Med Chem. 2000 Apr;8(4):699-706. doi: 10.1016/s0968-0896(00)00014-6.


6-Aza steroid analogues were synthesized as PI-PLC inhibitors. The most active compound, 3beta-hydroxy-6-aza-cholestane (1) showed potent PI-PLC inhibition (IC50 = 1.8 microM), similar to that of the commercially available steroid analogue U73122 (IC50 = 1-2.1 microM). Compound 1 exhibited significant growth inhibition effects (IC50 = 1.3 microM in each case) against MCF-7 and HT-29 cancer cells in in vitro cell culture. Compound 1 also inhibited the in vitro adhesion and transmigration of HT-1080 fibrosarcoma cells at 2.5 and 5.0 microM, respectively. In vivo, compound 1, at 1 mg/kg/day, reduced the volume of MCF-7 tumors in xenograft models, without weight loss in mice. Structure activity relationships of this series of compounds revealed that a hydrophobic cholesteryl side chain, 3beta-hydroxy group and a C-6 nitrogen containing a hydrogen atom at position-6 are crucial for activity. N-Maleic amidoacid derivative 11 also exhibited weak inhibition (IC50 = 16.2 microM).

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology*
  • Cholestanols / chemistry
  • Cholestanols / pharmacology*
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Phosphatidylinositol Diacylglycerol-Lyase
  • Phosphoinositide Phospholipase C
  • Spectrum Analysis
  • Tumor Cells, Cultured
  • Type C Phospholipases / antagonists & inhibitors*


  • 3beta-hydroxy-6-aza-cholestane
  • Antineoplastic Agents
  • Aza Compounds
  • Cholestanols
  • Enzyme Inhibitors
  • Type C Phospholipases
  • Phosphoinositide Phospholipase C
  • Phosphatidylinositol Diacylglycerol-Lyase